It is generally held that the central mechanism underlying the protean manifestations of the sickle cell syndromes involves an hypoxic-induced intracellular gelation process which critically alters normal blood rheology and results in vaso-occlusion to vital organs. However, actual blood vessel obstruction has been rarely demonstrated. With the development of new non-invasive imaging and para-imaging methods, it is now technically possible and feasible to characterize both regional organ perfusion and tissue biochemistry in quantitative terms, and in addition attempt to reconstruct the pathophysiologic events responsible for initiation, ischemia, infarction and resolution in these patients. This initiative represents an attempt to assess more objectively patients with sickle cell disease and related syndromes. Our goals are to develop ways to examine the pathophysiological processes in various organs, to develop quantitative ways to assess disease severity and progression, and to develop objective means to evaluate potential therapeutic approaches. Our main studies so far have focused on the use of anaerobic threshold measurements to gauge exercise tolerance. In preliminary analyses, we have found that the vasodilator, nifedipine, increases the time of exercise before the occurrence of sustained anaerobiosis. We have, in addition, early data on the permeability of retinal blood vessels in ten patients before and after various therapeutic interventions. Feasibility studies are currently underway to determine the utility of positron emission tomography, laser Doppler velocitometry and nuclear magnetic resonance imaging in patients with sickle cell disease. These studies should facilitate clinical trials of therapeutic agents designed to maintain or improve the biological integrity of jeopardized organs in patients with sickle cell disease. We plan to extend these studies to patients with other sickle cell syndromes.